Triazolo{8 4,3-d{9 {8 1,4{9 benzodiazepine-3,6-diones

ABSTRACT

Compounds having the structure   WHEREIN R1 is hydrogen, alkyl, phenyl, or benzyl, R2 is hydrogen or alkyl, R3 is nitrogen containing heterocyclic, R4 is hydrogen, halogen, nitro, cyano, trifluoromethyl, alkyl, alkoxy, or alkylthio, and n is 2, 3, or 4 are useful as anti-inflammatory agents.

TJ'nited States Patent [191 Wogt et a1,

[451 Tully 81,1975

[ 1 TR1AZOLO[4,3-D][1,4]BENZODIAZEPINE- 3,6-DIONES [75] Inventors: B. Richard Vogt, Yardley, Pa.; Peter C. Wade, Pennington, NJ.

[73] Assignee: E. R. Squibb & Sons, Tm,

Princeton, NJ.

22 Filed: Mar. 4, 1974 21 Appl. No.: 447,625

[52] US. C11 260/2393 T; 424/250; 424/267;

424/273; 424/274 [51] 11m. C1l C0701 57/02 [58] Field of Search 260/2393 T [56] References Cited UNITED STATES PATENTS 1/1973 Hester 260/308 R 2/1973 Hester 260/308 R Primary ExaminerHenry R. Jiles Assistant ExaminerRobert T. Bond Attorney, Agent, or FirmLawrence S. Levinson; Merle J. Smith; Donald .1. Barrack [57] ABSTRACT Compounds having the structure 4 Claims, No Drawings I TRIAZGLU [43-10] [ll ,4] BENZUDllAZlEPIlNlE-3,6-

lD llQNIES SUMMARY OF THE INVENTION Compounds having the structure and the pharmaceutically acceptable acid-addition salts thereof, are useful anti-inflammatory agents.

In formula l, and throughout the specification, the symbols are as defined below:

R, can be hydrogen, alkyl, phenyl, or benzyl;

R can be hydrogen or alkyl; R can be CHQ-(CHQM Cl-l -CH wherein A is Cll-llQ, oxygen or NQ, wherein Q is hydrogen or alkyl and wherein m is or 1;

R, can be hydrogen, halogen (preferably fluorine, chlorine or bromine), nitro, cyano, triflu0ro methyl, alkyl, alkoxy, or alkylthio; and

n can be 2, 3, or 4.

The term alkyl, as used throughout the specification, either by itself or as part of a larger group, refers to both straight and branched chain alkyl groups containing l, 2, 3, or 4 carbon atoms.

The term alkoxy, as used throughout the specification, refers to a group of the formula YO, wherein Y is alkyl as defined above.

The term halogen, as used throughout the specification, refers to fluorine, chlorine, bromine, and iodine.

Exemplary of the heterocyclic moieties contemplated by the formula are l-pyrrolidinyl, l-piperidinyl, 3-oxazolidinyl, 4- morpholinyl, l-imidazolidinyl, l-piperazinyl, 4-alkyl-lpiperazinyl, 3-alkyll -imidazolidinyl, 4-alkyll piperidinyl, and 3-alkyl-l-pyrrolidinyl.

DETAILED DESCRllPTlON OF THE lNVENTlON The novel compounds of this invention are produced from compounds having the formula D, II I 6 \I v r r l l T? '-l L 2 e, 2-:

10 wherein R can be halogen (preferably bromine or chlorine), sulfhydryl, alkoxy, alkylthio, or phenylalkylthio and R, can be alkyl, phenyl, or benzyl. The compounds of formula ll are known; see for example US. Pat. No. 3,414,563 and Swiss Pat. No. 485,742.

Reaction of a benzodiazepine of formua ll with an alkyl carbazate having the formula l-hN-Nll-llC-OZ, wherein Z is alkyl, yields a compound having the structure III '16 HN-N-C-OZ H H The reaction can be run without a solvent, or'in a nonreacting organic solvent, at a temperature of from about C to 250C for about 5 minutes to 24 hours, preferably from about C to C for about 30 minutes to 6 hours. The benzodiazepine of formula ll, and the alkyl carbazate are reacted in approximately a 1:1 molar ratio. Heating a compound of formula III at an elevated temperature, e.g., 80C to 200C, preferably lOOC to 180C, yields a compound having the strucin order to obtain the triazolobenzodiazepines of formula l, a triazolobenzodiazepine of formula IV is reacted with an appropriate base, e.g., thallous ethoxide, to obtain a salt having the structure "140C for 2 to 24.liours.

The salt of formula V is subsequently reacted with .a compound having the formula R -,(CI-I ),,X, wherein X can be chlorine, bromine, iodine, alkylsulfonate (e.g.,

methanesulfonate) or arylsulfonate (e.g., toluenesulfonate), to obtain a Compound having the structure The reaction of a triazolobenzodiazepine of formula IV with thallous ethoxide is run in a non-reactive polar sol vent, e.g., dimethylformamide, at a temperature of from about C to 180C, preferably at room tempera- I ture to 80C for aper'iod of about 1 minute to 5 hours,

preferably for minutes to 1 hour. The reaction of a salt of formula V with a compound of the structure R '('cH, ,,x is run atabout 50C .to 200C for a period of about 30 minutes to 72 hours, preferably at 80C to Alternatively, the compounds of formula Vlcan be prepared by first reactinga salt,.suc h as the salt of for- Y mula V, with a compound having the formula wherein X and n are as defined previously, to obtain compounds having the structure 6 VIII The reaction of a salt of formula V with a compound having the formula I-IO-(CI-I ),,-X is run at about 50C to 200C for a period of about 30 minutes to 72 hours, preferably at 80C to 140C for 2 to 24 hours.

The compounds of formula VIII can be converted to the corresponding compounds of formula VI using procedures well known in the art. The proton of the hydroxyl group in the compounds of formula VIII is first converted to a leaving group, e.g., by reacting the compounds with an alkyl (or aryl) sulfonyl halide in the presence of a non-reacting organic base. The resulting intermediate can then be converted to a compound of 4 formula VI by reacting it with an amine having the formula This reaction can be carried out in an organic solvent, e.g., toluene, at a temperature of from 25C to 200C for minutes to 24 hours, preferably at 80C to 150C for 1 hour to 5 hours.

Reduction of triazolobenzodiazepines of formula VI,

1 wherein R is benzyl, to yield compounds having the structure 3 x v I N O can be accomplished by reacting the compound with hydrogen under pressure in the presence of a catalyst, e.g., palladium or Raney nickel, or by reacting the compound with anhydrous, liquid hydrofluoric acid.

Compounds of formula I wherein R is hydrogen are I preferred.

Compounds of formula I wherein R is'in the 9 or 10- position are preferred, and those wherein R is in the lO-position are particularly preferred. Compounds of formula I wherein R is halogen or trifluoromethyl are preferred, chlorine being the most preferred halogen.

Compounds of formula'I wherein n is 2 or 3 are preferred. I i i The triazolobenzodiazepines of formula I form pharmaceutically acceptable acid-addition salts with inorganic and organic acids. These acid-addition salts, in addition to having the usefulpharmacological activity of the corresponding free base, frequently provide useful means for isolating the products from reaction mixtures by forming the salt in a medium in which it is insoluble. The free base may then be obtained by neutralization, e.g., with a base such as sodium hydroxide;

The triazoobenzoadiaz epines of formula' l, and the pharmaceutically acceptable acid-addition salts of the formulated for tablets, capsules, elixirs, or powders, or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice. The compounds of this invention may be administered in amounts of Z-(I-Fiperidinyhethyl chloride (1.5 equivalents) is added to a refluxing suspension of the thallium salt in 600 ml of toluene. After 2 hours of reflux, another equal amount of 2-(l-piperidinyl)ethyl chloride is 100 mg/70kg/day to 2 g/70kg/day, preferably 100 5 added and the refluxing is continued for 5 hours. mg/70kg/day to 1 g/70kg/day. The reaction mixture is cooled to room temperature The following examples are specific embodiments of and filtered through infusorial earth to remove the thalthis invention. lium salts. The infusorial earth is washed by stirring in benzene and filtered through fresh infusorial earth. The EXAMPLE 1 two solutions are combined and passed through a 12X4.5 cm column of magnesium silicate. The column y y -[2-( is further eluted with about 3 liters of ethtyl acetate. piperidinyl)ethyl]-3H-s-triaZ0l0[4,3-d]- After combining the solutions, the solvents are re- [1,4]benzodiazepine-3,6(5H)-dione moved under vacuum to yield the product.

5 ,7-1Dichloro-1,3-dihydro-1-methyl-2H-1,4- EXAMPLE 2 benzodiazepin-Z-one (50 g) and ethylcarbazate (43 g) 1() Ch1 2,7 dih d -7 h 1 2 [3-( 1- are refluxed in 2,000 ml of toluene for 4 hours. The tolpiperidinyl)propyl]-3H-s-triazolo[4,3-d][1,4]benuene is decanted from the insoluble mixture and re- Z0diazepine-3,6(SIHD-dione moved under vacuum, producing a white powder which 1 2 7 7 1 3H i 1 [4 3 is freed from the accompanying viscous material by d] [1 4]b di i 3 6(5H) di (164 g, stirring with acetonitrile. The white powder is insoluble pared as described in Example 1A) is dissolved in 40 and is filtered off; the filtrate is saved. ml of dimethylforrnamide at 70C. Thallous ethoxide The residue from the original reaction mixture is reg) is added dropwise t0 the Solution While Stirfl d f 4 hours in momma The solvent is then ring. After the thallous ethoxide is added, stirring is moved under vacuum leaving a white powder which is cogtmued for 45 mmutesi the mixture 15 coffled to stirred with acetonitrile to remove viscous impurities. S n 200 ml of ether ls added' The resulting y clpltate IS filtered off and dried at 25C under vacuum This mixture 18 filtered, the White powder combined for 4 hours to yield 4.5 g of the thallium salt. with the powder obtalned previously (total g) and p y p py chloride (15 equivalents) is recrystallized from methanol-droxane to yield the added to a refluxing Solution of the thallium Salt title Compound melting Point 2680-26900 pared above in 150 ml of toluene. After 3 hours of re- Both acetonitrile filtrates are combined, stripped and fl an equal amount f 3 (1 i idi 1) 1 h1 h ated at about C for 2 days. This process yields 35 ride is added and the refluxing is continued for 5 hours. another 5.5 g of product. The reaction mixture is cooled to room temperature and filtered through infusorial earth to remove the thallium salts. The infusorial earth is washed by stirring in lO'ChIOTO'Zi7dihydl'o'7'methyl'z[2'( l'piperidinyn' 4O toluene and filtered through fresh infusorial earth. The y lll 1,4]benZ0diaZePine'36- two solutions are combined and passed through a 12 3 (5H)-dione cm column of magnesium silicate. The column is fur- 1O ChlOl O 2,7 dihydro 7 methyl 3H s triazolo[4,3 ther eluted with about 3 liters of ethyl acetate. After combining the solutions, the solvents are removed dil[ 1,4lbenzodiazep1ne-3,6(5H)-d1one (7.92 g) 15 susunder vacuum to yield the product pended in ml of tetrahydrofuran. Thallous ethox- 45 ide (7.5 g) is added dropwise to the suspension while EXAMPLES 3-13 stirring. After the thallous ethoxide is added, stirring is Following the procedure f g l 1 b b i continued for 45 minutes and the mixture is then fili h Compounds i di d i column 1 b l f 5 7- tered. The filter cake is washed by stirring as a slurry 5O dichloro-l ,3-di11ydro-1-methy1-2lr1-1,4-benzodiazepinwith ether, and filtered to yield 13.5 g of the thallium Z-one, the compounds indicated in column 111 are obsalt. tained.

Example Column 1 Column 11 3 1-benzyl-5-chloro-l,3-dihydro-7- 7-benzyl-2,7-dihydro-2-[2-( l-piperidiazepin-2-one 4 5-chloro-1 ,3-dihydro l -methyl-7- nitro2H- 1 ,4-benzodiazepin2-one 6 5-chloro-l,3-dihydro-1,7-dimethyl- 21-1-1,4-benzodiazepin-2-one diazepin-Z-one 8 8-bromo-5-ethoxy-l ,3-dihydro-1- phenyl-2H-l ,4-benzodiazepin-2-one Example Continued Column 1 Column ll 9 l-benzyl-7-cyano-l .3-dihydro-5- (2methylthio)-2H-l ,4-benzodiazepin- -one l-benzyl-7-chloro-l .3-dihydro- 21-1-1,4-henzodiazepin-2-one-5- thione 5-chloro-7-ethyll ,3-dihydrol-phenyl-Zl-ll .4-benzodiazepin- Z-one S-chlorol -ethyll ,3-dihydro-2H- 1,4-benzodiazepin-2-one 5-chloro-l,3 dihydro-7-(methoxy)- l-methyl-2H-1,4-benzodiazepin-2- one dione Example EXAMPLES 14-16 Following the procedure of Example 2, but substituting the compounds indicated in column I below for 3- (l-piperidinyhpropyl chloride, the compounds indicatedin column 11 are obtained.

Column 1 Column ll 14 3-( l-pyrrolidinyDpropyl chloride dion l 3-( 3-oxazoliclinyl)propyl chloride drone 16 4-( l-imidazolidinyl)butyl chloride l-chloro-2,7-dihydro-7-methyl-2-[ 4- drone EXAMPLE l7 10-Chloro-2,7-dihydro-2-[3-( 1-piperidinyl)propy1]- 3H-s-triazolo[4,3-d][ 1 ,4]benzodiazepine-3,6(H)- dione A. 7-Benzyl- -chloro-2,7-dihydro-3H-s-triazolo-[4,3- d][ 1,4]benzodiazepine-3,6(5H)-dione l-Benzyl-S ,7-dichloro- 1 ,3-dihydro-2H- 1 ,4- benzodiazepin-Z-one (0.10 mole) and ethyl carbazate (0.11 mole) are mixed together in 400 ml of dimethylformamide for minutes while heating at 130C to yield 7-benzy1- 1 0-ch1oro-2,7-dihydro-3l-l-striazolo[4,3-d][ 1,4]benzodiazepine-3,6(5H)-dione.

7-Benzyll 0-ch1oro-2,7-dihydro-3 H-s-triazolo 4, 3 d]-[1,4]benzodiazepine-3,6(5H)-dione (0.02 mole) is dissolved in 100 ml of dimethylformamide at 70C. Thallous ethoxide (0.02 mole) is added to the solution and stirred for 1 hour at room temperature. The solution is diluted with 300 ml of ether, and the precipitated salt is filtered off.

3-(l-Piperidinyl)propyl chloride (1.5 equivalents) is added to a refluxing solution of the thallium salt prepared above in 150 ml of toluene. After 3 hours of reflux, an equal amount of 3-(1-piperidinyl)propyl chloride is added and the refluxing is continued for 14 hours. i 1

cm column of magnesium silicate. The column is further eluted with about 3 liters of ethyl acetate. After combining the solutions, the solvents are removed under vacuum to yield 7-benzyl-10-ch1oro-2,7-dihydro- 2-[ 3-( 1-piperidinyl)propyl]-3H-triazolo[4,3-

d] 1,4]benzodiazepine-3 ,6(5H)-dione.

C. l0-Chloro-2,7-dihydro-2-[ 3-( 1-piperidiny1)propy1]- 3H-s-triazolo[4,3-d][ 1 ,4]benzodiazepine-3,6(5H)- dione 7-Benzy1-10-chloro-2,7-dihydro-2-[3-( lpiperidinyl )-propy1]-3H-s-triazolo[4,3-d][ 1,4]benzodiazepine-3,6(5H)-dione (0.01 mole) is hydrogenated at C in 300 ml of acetic acid containing 0.3 g of pre-reduced Raney nickel. The initial hydrogen pressure is 60 psi. The reduction is stopped after 0.01 mole of hydrogen is absorbed, the catalyst is filtered off, and the solvent is evaporated. The residue is stirred with water and 10-chloro-2,7-dihydro-2-[3-( lpiperidinyl)propyl]-3H-s-triazolo[4,3-d][ 1 ,4]benzodiazepine-3,6(5H)-dione is filtered off and dried.

EXAMPLES 18-20 Following the procedure of Example 17, but substituting the compound indicated in column I below for 1 -benzyl-5 ,7-dich1oro-1,3-dihydro-2H-1,4- benzodiazepin-Z-One and the compound indicated in column 11 below for 3-(1-piperidinyl)propyl chloride, the compound indicated in column III is obtained.

Column 1 Column 11 Column 111 l-bcnzyl-S-chlorol ,3- dihydro-7-(methoxy)-2H- 1 ,4-bcnzodiazepin-2-one 2-( 4-morpholinyl ethyl chloride dinyl)ethyl chloride dinzepin-2-onc [1,4]bcnzodiazcpine-3,6(5H) dion EXAMPLE 21 10-Chloro-2,7-dihydro-7-methyl-2-[ 3-( 1- piperazinyhpropyl]-3H-s-triazolo[4,3-d][ l ,41benzodiazepine-3,6(5l'll)-dione A. 10-Chloro-2,7-dihydro-2-( 3-hydroxypropyl)-7-methyl- 3l'l-s-triazolo[4,3-d][1,4]benzodiazepine-3,6(5H)- dione l-Chloro-2,7-dihydro-7-methyl-3H-s-triazolo-[4,3- d]-[1,4]benzodiazepine-3,6(H)-dione (7.92 g, prepared as described in Example 1A) is suspended in 120 ml of tetrahydrofuran. Thallous ethoxide (7.5 g) is added dropwise to the suspension while stirring. After the thallous ethoxide is added, stirring is continued for 45 minutes and the mixture is then filtered to yield the thallium salt.

To a stirring, refluxing suspension of 3 g of the thallium salt in toluene is added 3 ml of 1-chloro-3- hydroxypropane. After refluxing for 72 hours, another 3 ml of the chloro alcohol is added and heating is continued for another 24 hours. The solution is cooled to room temperature and filtered through infusorial earth to remove the thallium salts. The infusorial earth is washed by stirring in toluene and then filtered through fresh infusorial earth. The two solutions are combined and passed through a 12 3 cm column of magnesium silicate. The column is further eluted with about 3 liters of ethyl acetate. After combining the solutions, the solvents are removed under vacuum to yield the product.

-Chloro-2,7-dihydro-7-methyl-2- 3-(ptoluenesulfonyloxy)propyl]-3l-l-s-triazolo[4,3-d][ l ,4]- benZodiazepine-3,6(5li-ll)-dione l0-Chloro2,7-dihydro-2-( 3-hydroxypropyl )-7- methyl-3H-s-triazolo[4,3-d][ 1,4]benzodiazepine- 3,6(5l'1)-dione (1.0 mole) and p-toluenesulfonyl chloride (0.20 mole) are added to 150 ml of pyridine. The reaction mixture is stirred at 5C for 24 hours. The reaction is poured into 700 ml of water and the resulting precipitate is filtered off. The filter cake is washed with fresh water, filtered off and dried at 25C under vacuum for 24- hours to yield the title compound.

C. l0-Chloro-2,7-dihydro-7-methyl-2-[ 3-( 1-piperazinyl)- propyl ]-3ll-ll-s-triazolo[4,3-d][ 1 ,4]benzodiazepine-3 ,6-

(5H)-dione l0-Chloro-2,7-dihydro-7-methyl-2-[3-(ptoluenesulfonyloxy)propyl]-3H-s-triazo1o[4,3- d][1,4]benzodiazepine-3,6(5l-l)-dione (0.05 mole) and piperazine (0.1 mole) are refluxed in 600 ml of toluene for 3 hours. The reaction mixture is cooled to 25C and the resulting precipitate is filtered off. The product is extracted from the toluene filtrate into 10% hydrochloric acid. The acid solution is made basic with 10% sodium bicarbonate and the product is extracted into chloroform. The solvent is removed under vacuum, and the residue is recrystallized from ethanol and dried under vacuum at 40C for 3 hours to give the title compound.

What is claimed is:

11. A compound having the formula or a pharmaceutically acceptable acid-addition salt thereof, wherein R is hydrogen, alkyl, phenyl or benzyl; R is hydrogen or alkyl;

CHZ CHZ R3 is N\CH2 CH2/A wherein A is Cll-llQ, oxygen or NQ, Q is hydrogen, alkyl or phenyl, and m is 0 or 1; R is hydrogen, halogen, nitro, cyano, trifluoromethyl, alkyl, alkoxy, or alkylthio; and n is 2, 3, or 4; wherein alkyl is alkyl of 1 to 4 carbon atoms and alkoxy is alkoxy of l to 4 carbon atoms.

2. A compound in accordance with claim 1 wherein R is alkyl, phenyl or benzyl.

3. A compound in accordance with claim 11 wherein R is hydrogen.

4. A compound in accordance with claim 11 wherein R is hydrogen.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENTNO. 3,894,011 Q DATED July 8, 1975 INV ENTOR(S) B. Richard Vogt and Peter C. Wade It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

8 Column 2, line 16, "H NNHC-OZ" should read H N-NHC-OZ.

Column 4, line 58, "triazoobenzoadiazepines" should read triazolobenzodiazepines.

Column 5, Example 1 should read:

Example 1 l0-Chloro-2,7-dihydro-7-methyl-2- [2- (lpiperidinyl) ethyl]- 3Il s triazolo [4 ,3-d] [l,4]benzodiazepine-3,6 (5t) dione A. lO-Chloro-2,7dihydro7-methyl-3I-l-s-triazolo [4,3-d] [1,4]-

benzodiazepine 3,6 (5I )dione.

o Signed and Scaled this fourth D a) of November 1975 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Anesting Officer Commissioner nfPatems and Trademarks 

1. A COMPOUND HAVING THE FORMULA
 2. A compound in accordance with claim 1 wherein R1 is alkyl, phenyl or benzyl.
 3. A compound in accordance with claim 1 wherein R1 is hydrogen.
 4. A compound in accordance with claim 1 wherein R2 is hydrogen. 